Drug action enzymes

E (1997) Mechanism of action of dietary chemoprotective agents in rat liver induction of phase I and II drug metabolizing enzymes and aflatoxin B1 metabolism . Carcinogenesis, 18 1729-38. 

In contrast to the effects obtained with viruses mentioned earlier, rous sarcoma virus (RSV) is inactivated by direct contact with 2 [81]. Evidence for the drug action by a chelate compound was obtained by using concentrations of 3a and copper(II) sulfate, neither of which individually affected enzyme activity or transforming abilities [82]. In a later study these workers showed that several metal complexes inhibit the RNA dependent DNA polymerases and the transforming ability of RSV, the most active compound being a 1 1 copper(II)... 

While the main focus of this chapter has been on enzymes as the primary molecular targets of drug action, it is worthwhile noting that the quantitative evaluation of enzyme activity has other important roles in drug discovery and development. 

Mechanisms of drug action. To mediate a response the drug can bind to the desired therapeutic target or to other molecular targets such as G-protein-coupled receptors (GPCRs), ion channels, or transporters on the cell membrane, or to intracellular targets such as enzymes and nuclear hormone receptors. 

Caco-2 cells cultured on filters achieve a monolayer density, and exhibit morphological characteristics similar to enterocytes such as tight intercellular junctions and highly developed microvilli.13-15,42 Transport of drugs across Caco-2 monolayers is limited by the action of biochemical and physical barriers (Figure 9.2). The biochemical component comprises drug-metabolizing enzymes, uptake transporters, and efflux transporters.17,19-23,28,30 The... 

The enzymatic conversion of many analogues of the naturally occurring purines directly to their biologically active form, the ribonucleotides, in vivo [5, 8, 10, 13, 39] underlines the importance of these enzymes to the drug action of this class of compounds. 2-Aminoadenine (2, 6-diaminopurine, I) [107], 2-fluoroadenine (II) [108], 4-aminopyrazolo [3, 4-d] pyrimidine (VIll) [109]. and 2- and 8-aza-adenine (IX and X) [ 110, 111] have all been shown to be substrates for the adenine phosphoribosyltransferase [J12, 113]. Extensive studies on the metabolism of 2-aminoadenine (I) in E. coli [114, 115], L cells [116], and mice [117] have also shown its conversion by this enzyme to the ribonucleotide. 

Acetylcholinesterase is a remarkably efficient enzyme turnover has been estimated as over 10 000 molecules per second at a single active site. This also makes it a key target for drug action, and acetylcholinesterase inhibitors are of considerable importance. Some natural and synthetic toxins also function by inhibiting this enzyme (see Box 7.26). 

To make quantitative predictions of DDI for the new compound as perpetrator, a reliable estimate of a relevant in vivo concentration is needed. What is tmly needed is knowledge of the concentration of the inhibitor available to bind to the enzyme. For liver, if the well accepted free-dmg hypothesis (which underwrites fundamental drug action principles in pharmacology) is applied for DDI, then the use of a free intracellular liver concentration is needed. For inhibitors that are permeable through membranes, the free concentration in the portal vein should serve as the closest proxy for free intracellular concentration in the liver. Diminished permeability as well as active uptake and efflux from liver cells can confound this relationship. Nevertheless, use of estimates of unbound portal vein concentrations (which can be estimated from... 

L A. When one inhibits the action of a drug-metabolizing enzyme (A), one would expect an increase instead of a decrease in drug concentrations, since less is being metabolized. Induction of an enzyme (B) would have the opposite effect, since there would be more enzyme available to metabolize the drug. 

Since the enzyme that converts dopamine to norepinephrine (dopamine (3-hydroxylase) is located only within the vesicles, the transport of dopamine into the vesicle is an essential step in the synthesis of norepinephrine. This same transport system is essential for the storage of norepinephrine. There is a tendency for norepinephrine to leak from the vesicles into the cytosol. If norepinephrine remains in the cytosol, much of it will be destroyed by a mitochondrial enzyme, monoamine oxidase MAO). However, most of the norepinephrine that leaks out of the vesicle is rapidly returned to the storage vesicles by the same transport system that carries dopamine into the storage vesicles. It is important for a proper understanding of drug action to remember that this single transport system, called vesicular transport, is an essential element of both synthesis and storage of norepinephrine. 

Since allopurinol is metabolized by the hepatic microsomal drug-metabohzing enzymes, coadministration of drugs also metabohzed by this system should be done with caution. Because allopurinol inhibits the oxidation of mercaptopurine and azathioprine, their individual administered doses must be decreased by as much as 75% when they are given together with allopurinol. Allopurinol may also increase the toxicity of other cytotoxic drugs (e.g., vidarabine). The actions of allopurinol are not antagonized by the coadministration of salicylates. 

Nunoura, C. Umezawa, and K. Z0246 Yoneda. Studies on effect of crude drugs on enzyme activities. 1. Influence of cinnamon bark upon protein diges- Z0247 tive action by pancreatin. Shoyaku-gaku Zasshi 1982 36 11-16. 

---